Zebrafish Vascular Development: General and Tissue-Specific Regulation

Circulation is required for the delivery of oxygen and nutrition to tissues and organs, as well as waste collection. Therefore, the heart and vessels develop first during embryogenesis.The circulatory system consists of the heart, blood vessels, and blood cells, which originate from the mesoderm. The gene expression pattern required for blood vessel development is predetermined by the hierarchical and sequential regulation of genes for the differentiation of mesodermal cells. Herein, we review how blood vessels form distinctly in different tissues or organs of zebrafish and how vessel formation is universally or tissue-specifically regulated by signal transduction pathways and blood flow. In addition, the unsolved issues of mutual contacts and interplay of circulatory organs during embryogenesis are discussed.

Zebrafish Vascular Development: General and Tissue-Specific Regulation

Circulation is required for the delivery of oxygen and nutrition to tissues and organs, as well as waste collection. Therefore, the heart and vessels develop first during embryogenesis.The circulatory system consists of the heart, blood vessels, and blood cells, which originate from the mesoderm. The gene expression pattern required for blood vessel development is predetermined by the hierarchical and sequential regulation of genes for the differentiation of mesodermal cells. Herein, we review how blood vessels form distinctly in different tissues or organs of zebrafish and how vessel formation is universally or tissue-specifically regulated by signal transduction pathways and blood flow. In addition, the unsolved issues of mutual contacts and interplay of circulatory organs during embryogenesis are discussed.

AKAP12 regulates vascular integrity in zebrafish

The integrity of blood vessels controls vascular permeability and extravasation of blood cells, across the endothelium. Thus, the impairment of endothelial integrity leads to hemorrhage, edema, and inflammatory infiltration. However, the molecular mechanism underlying vascular integrity has not been fully understood. Here, we demonstrate an essential role for A-kinase anchoring protein 12 (AKAP12) in the maintenance of endothelial integrity during vascular development. Zebrafish embryos depleted of akap12 (akap12 morphants) exhibited severe hemorrhages. In vivo time-lapse analyses suggested that disorganized interendothelial cell-cell adhesions in akap12 morphants might be the cause of hemorrhage. To clarify the molecular mechanism by which the cell-cell adhesions are impaired, we examined the cell-cell adhesion molecules and their regulators using cultured endothelial cells. The expression of PAK2, an actin cytoskeletal regulator, and AF6, a connector of intercellular adhesion molecules and actin cytoskeleton, was reduced in AKAP12-depleted cells. Depletion of either PAK2 or AF6 phenocopied AKAP12-depleted cells, suggesting the reduction of PAK2 and AF6 results in the loosening of intercellular junctions. Consistent with this, overexpression of PAK2 and AF6 rescued the abnormal hemorrhage in akap12 morphants. We conclude that AKAP12 is essential for integrity of endothelium by maintaining the expression of PAK2 and AF6 during vascular development.

Tie2 is tied at the cell-cell contacts and to extracellular matrix by Angiopoietin-1

Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase. Ang1-Tie2 signal has been proposed to exhibit two opposite roles in the controlling blood vessels. One is vascular stabilization and the other is vascular angiogenesis. There has been no answer to the question as to how Tie2 induces two opposite responses to the same ligand. Our group and Dr. Alitalo's group have demonstrated that trans-associated Tie2 at cell-cell contacts and extracellular matrix (ECM)-anchored Tie2 play distinct roles in the endothelial cells. The complex formation depends on the presence or absence of cell-cell adhesion. Here, we review how Ang1-Tie2 signal regulates vascular maintenance and angiogenesis. We further point to the unanswered questions that must be clarified to extend our knowledge of vascular biology and to progress basic knowledge to the treatment of the diseases in which Ang1-Tie2-mediated signal is central.